Most biochemical processes require the production and degradation of proteins, a task that weighs heavily on the cell. Our understanding of the physiochemical reactions that limit the assembly and cellular processing of integral membrane proteins remains superficial. Furthermore, mutations that compromise this process can burden cellular protein homeostasis (proteostasis) in a manner that contributes to a number of diseases. To gain insight into these fundamental processes, we assessed the relationship between the conformational stability of a eukaryotic membrane protein and the degree to which it is retained in the secretory pathway by cellular quality control. We quantitatively assessed both the conformational equilibrium and cellular trafficking of 12 variants of the a-helical membrane protein peripheral myelin protein 22 (PMP22), the intracellular misfolding of which is known to cause peripheral neuropathies associated with Charcot-Marie-Tooth disease (CMT). We show that the extent to which these mutations influence the energetics of PMP22 folding is proportional to the observed reduction in cellular trafficking efficiency. Strikingly, quantitative analyses also reveal that the reduction of motor nerve conduction velocities in affected patients is proportional to the extent of the mutagenic destabilization. Preliminary investigations reveal that the interaction of nascent PMP22 with lectin chaperones imposes a key bottleneck in PMP22 biogenesis. Together these findings provide compelling evidence that the effects of these mutations on the energetics of PMP22 folding lie at the heart of the molecular basis of CMT and highlight conformational stability as a key factor governing membrane protein biogenesis.